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p57 Kip2 Beckwith-Wiedemann Syndrome

p57 Kip2 Beckwith-Wiedemann Syndrome. Chris Joubert March 31, 2005. Beckwith-Wiedemann Syndrome (BWS). Hans-Rudolf Wiedemann (1964) and J. Bruce Beckwith (1969) Congenital exomphalos, macroglossia, and gigantism In the US: US frequency is estimated at 1 in 15,000 live births.

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p57 Kip2 Beckwith-Wiedemann Syndrome

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  1. p57Kip2 Beckwith-Wiedemann Syndrome Chris Joubert March 31, 2005

  2. Beckwith-Wiedemann Syndrome (BWS) • Hans-Rudolf Wiedemann (1964) and J. Bruce Beckwith (1969) • Congenital exomphalos, macroglossia, and gigantism • In the US: US frequency is estimated at 1 in 15,000 live births. • Children affected with BWS have a propensity to develop tumors such as Wilms’ tumor, hepatoblastoma, and rhabdomyosarcomas. http://www.emedicine.com/ped/topic218.htm Mainprize et al. (2001) J Neuro-Oncol 51:205-218

  3. Beckwith-Wiedemann Syndrome • Approximately 80% of BWS patients demonstrate genotypic abnormalities of the distal region of chromosome arm 11p • The BWS region of 11p was the first identified example of imprinting in mammals • Several 11p genes are imprinted, including p57,IGF2, and H19. http://www.emedicine.com/ped/topic218.htm Mainprize et al. (2001) J Neuro-Oncol 51:205-218

  4. Imprinting Only one allele is expressed Paternal Maternal

  5. p57 - Lessons from Knockout Mice P57-/- - Embryonic/neonatal lethality, Multiple developmental defects, altered cellular proliferation Mainprize et al. (2001) J Neuro-Oncol 51:205-218 Nakayama et al. (1998) BioEssays 20:1020-1029

  6. Mice Knockouts • Similarities to BWS • Omphalocele • Enlargement of the adrenal cortex, adrenal cytomegaly, and renal medullary dysplasia Zhang et al. (1997) Nature 387:151-158

  7. p57 • Member of family of Cip/Kip inhibitors along with p21Cip1 and p27Kip2 • Inhibit wide range of CDKs and bind to both the cyclin and cyclin-dependant kinase. • Cip/Kip inhibitors are not specific to any particular cyclin/CDK complex. Mainprize et al. (2001) J Neuro-Oncol 51:205-218

  8. p57 • 316 Amino-acids • Performs majority of function in nucleus and contains nuclear localizing sequences at C-terminal end. CDK Inhibitory Domain Proline Rich Domain Acidic Domain QT Domain Nakayama et al. (1998) BioEssays 20:1020-1029 Mainprize et al. (2001) J Neuro-Oncol 51:205-218

  9. Russo et al. (1996) Nature 382:325 CDK Inhibitory Domain

  10. CDK2 Cyclin A • CDK inhibitory domain binds conserved cyclin box of cyclin and binds CDK, occupying its catalytic cleft Russo et al. (1996) Nature 382:325

  11. Cyclin D/ E p57Kip2 CDK 4/2 Courtesy of Dr. Duronio

  12. Mainprize et al. (2001) J Neuro-Oncol 51:205-218

  13. p57 How does this relate to cancer?

  14. p57 and cancer • P57Kip2 localizes to chromosome 11p15.5, a region containing several imprinted genes. • Paternal allele of p57Kip2 is transcriptionally silent in mice and humans. • 800 Kbp centromeric to the gene encoding insulin-like growth factor-2 (IGF-2), which is also imprinted and expressed only by the paternal allele Mainprize et al. (2001) J Neuro-Oncol

  15. Mechanisms for downregulation of p57 in BWS • Maternally inherited mutations • 5-10% - sporadic • 30-50% - familial • IGF-2 downregulates mRNA expression of p57Kip2 • -Increased levels of IGF-2 caused by one of three possible events: • 1) Mutation in Igf2R gene – IGF2R decreases levels of IGF-2 • 2) Loss of imprinting (LOI) of IGF-2 • 3) Inherit 2 paternal alleles Joyce et al. (1997) Hum. Mol. Genet. 6:1543 Mainprize et al. (2001) J Neuro-Oncol

  16. Cyclin D/ E p57Kip2 CDK 4/2 Courtesy of Dr. Duronio

  17. Mainprize et al. (2001) J Neuro-Oncol 51:205-218

  18. Summary • Exomphalos, macroglossia, gigantism • Mouse knockouts • Cip/Kip inhibitor • Cancer • Complete loss • Chronic low levels

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